The invention relates to a process for producing injectable medicament preparations which comprise a therapeutically and/or diagnostically effective substance which consists of an active compound, a spacer molecule and at least one protein-binding molecule and, after having been brought into contact with the body, binds covalently, by way of the protein-binding molecule, to body fluid constituents or tissue constituents, thereby creating a transport form of the active compound which can be hydrolytically or enzymically cleaved, in a pH-dependent manner, in the body with the active compound being released.
Most of the drugs which are used at present are low molecular weight compounds and, after having been administered systemically, exhibit high plasma and total clearances. Furthermore, as a result of diffusion processes, they penetrate into the tissue structures of the body and as a rule have a uniform biodistribution. These two properties lead to only small quantities of the drug reaching the site of action and, because of its distribution over the healthy tissue of the body, the drug gives rise to side-effects. These disadvantages are particularly pronounced in the case of those drugs which possess a high cytotoxic potential, such as cytostatic agents, immunosuppressive agents or virostatic agents.
Several strategies are pursued for improving the selectively of low molecular weight drugs, for example the chemical derivatization of basic structures, formulation as prodrugs, or the coupling of the drugs to carrier molecules. The present invention takes as its starting point those concepts in which drugs have been chemically bonded to endogenous macromolecules. Conjugates are known in which what are in general cytostatic agents are bound to serum proteins, predominantly to particular carrier molecules such as human serum albumin and human serum transferin, and then administered. These known protein conjugates are prepared either by coupling the cytostatic agent to the serum protein ex vivo in a “one pot method” (DE 41 22 210 A1), and isolating the resulting albumin-cytostatic agent conjugate, or by firstly derivatizing the cytostatic agent with a suitable spacer molecule, isolating the resulting product and, in a second step, coupling the cytostatic agent which has been derivatized in this way to the protein by way of a maleimide group (DE 196 36 889 A1 and PCT/DE97/02000) and then isolating the resulting albumin-cytostatic agent conjugate. Both methods suffer from the disadvantage that they use plasma proteins, which may contain pathogens. Other disadvantages of the above-described protein-active compound conjugates are their unsatisfactory stability and shelf-life and the technical input required for preparing them.
The invention is based on the object of overcoming these disadvantages. This object is achieved by means of a process for producing an injectable medicament preparation, comprising a therapeutically and/or diagnostically effective substance which is dissolved in an injectable carrier liquid, which process is characterized in that use is made, as the therapeutically and/or diagnostically effective substance, of a compound which consists of an active compound and at least one protein-binding molecular residue which are linked by way of a spacer, in which the spacer, or the bond between the active compound and the spacer, can be cleaved hydrolytically or enzymatically in the body in a pH-dependent manner. The active compound, or a derivative of the active compound, is released during the cleavage. An active compound derivative is understood as meaning substances which include the active compound but which may additionally contain parts of the spacer or of the groups by which the active compound was bonded to the protein-binding molecule. The activity of the active compound should not be impaired as a result of being released as a derivative. The active compound, or its derivative, preferably only displays its activity after having been released.
The invention is based on the surprising observation that it is not necessary, as had previously been assumed, to link an active compound to a particular carrier under defined conditions and then to administer the product but that, on the contrary, it is possible to employ therapeutically and/or diagnostically effective substances, which consist of a pharmacological active compound and at least one protein-binding molecular moiety, which are linked to each other by way of a spacer, directly as injectable medicaments since these medicaments, after having been brought into contact with the body, bind covalently, by way of the protein-binding molecule, to body fluid or tissue constituents, predominantly to serum proteins, such that a transport form of the active compound is created in vivo, which transport form reaches the cells or the tissue which is/are the target of the active compound. Since, in the case of the substance which is therapeutically and/or diagnostically effective, the bond in the spacer molecule, or between the active compound and the spacer molecule, can be cleaved, according to the invention, hydrolytically or enzymatically in the body in a pH-dependent manner, the active compound is nevertheless released, in a selective manner, at the desired target site.
Because of their protein-binding properties, injectable medicament preparations, which are obtained in accordance with the invention, of therapeutically and/or diagnostically effective substances decisively alter and improve the pharmacokinetic profile of the active compounds. When these therapeutically and/or diagnostically effective substances arrive in body fluids, they bind covalently to body fluid or tissue constituents, preferably to serum proteins, more preferably to serum albumin, in order, in this way, to be present as macromolecular prodrugs which transport the active compound to the target site and/or release it in a metered form.
The therapeutically and/or diagnostically effective substance which is obtained in accordance with the invention consists of an active compound A, a spacer molecule SM and at least one protein-binding molecule PM, having the following general structure:

In addition, the substance which is obtained in accordance with the invention can possess labelling groups or labelled elements or molecules, with the substance then being particularly suitable for diagnostic purposes. Preferred labels are one or more radionuclides, one or more ligands comprising radionuclides, one or more positron emitters, one or more NMR contrast agents, one or more fluorescent compound(s) and/or one or more contrast agents in the near IR range.